Oxidation of fluphenazine decanoate, a member of the neuroleptic phenothiazine
drugs, is believed to occur in oily solution via the hydroperoxides formed
as a result of autoxidation of the oil. Synthesis and characterisation of the
expected oxidation products of the drug was undertaken so that the formation of
these degradation products in oily solution, could be accurately determined. By
this means the rate of oxidation of fluphenazine decanoate by various hydroperoxides
was determined. Only in the case of the C-IB unsaturated fatty esters
did the overall oxidation process obey simple kinetics (2nd order) enabling values
for the respective rate-constants to be calculated. The presence of acid was
clearly demonstrated to catalyse oxidation of the tertiary amine centres in the
molecule, a finding contrary to reports in the literature. In addition, the catalytic
effect was shown to be related to the pKa value of the acid.
Benzyl alcohol is commonly added as a preservative to oily formulations and
thus the effect of this material on the rate of fluphenazine decanoate oxidation
was investigated. Evidence for the enhanced oxidation of the drug in the presence
of benzyl alcohol in a naturally ageing formulation was obtained and a plausible
mechanism for this phenomenon was sought. Autoxidation of the benzyl alcohol
was deemed a likely explanation and since little information on this aspect of
benzyl alcohol chemistry could be found in the literature an extensive study of
benzyl alcohol autoxidation was conducted. It was finally concluded that
autoxidation of benzyl alcohol leads directly to hydrogen peroxide offering one
viable explanation of the enhanced degradation of the drug observed in the
presence of the preservative.